Process for the preparation of macrolide antibacterial agents

ABSTRACT

Described herein are processes for the preparation of compounds of formula (I): and pharmaceutically acceptable salts, solvates, and hydrates thereof.

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims the benefit under 35 U.S.C. §119(e) of U.S.Provisional Application Ser. No. 60/982,446, filed Oct. 25, 2007, thedisclosure of which is hereby incorporated herein by reference.

TECHNICAL FIELD

The invention described herein relates to processes for preparingmacrolide antibacterial agents. In particular, the invention relates tointermediates and processes for preparing ketolides and other macrolidesthat include a 1,2,3-triazole substituted side chain.

BACKGROUND AND SUMMARY

The use of macrolides for various infectious diseases is well known.Erythromycin was the first compound of this class to be introduced intoclinical practice. Since then, additional macrolides, includingketolides have garnered much attention for their ability to treat a widerange of disease states. In particular, macrolides are an importantcomponent of therapies for treating bacterial, protozoal, and viralinfections. In addition, macrolides are often used in patients allergicto penicillins.

Illustrative of their wide ranging uses, macrolide compounds have beenfound to be effective for the treatment and prevention of infectionscaused by a broad spectrum of bacterial and protozoal infections. Theyare also useful for infections of respiratory tract and soft tissueinfections. Macrolide anitbiotics are found to be effective onbeta-hemolytic streptococci, pneumococci, staphylococci and enterococci.They are also found to be effective against mycoplasma, mycobacteria,some rickettsia, and chlamydia.

Macrolide compounds are characterized by the presence of a large lactonering, which is generally a 14, 15, or 16-membered macrocyclic lactone,to which one or more saccharides, including deoxy sugars such ascladinose and desosamine, may be attached. For example, erythromycin isa 14-membered macrolide that includes two sugar moieties. Spiramycinbelongs to a second generation of macrolide compounds that include a16-membered ring. Third generation macrolide compounds include forexample semi-synthetic derivatives of erythromycin A, such asazithromycin and clarithromycin. Finally, ketolides represent a newerclass of macrolide antibiotics that have received much attentionrecently due to their acid stability, and most importantly due to theirexcellent activity against organisms that are resistant to othermacrolides. Like erythromycins, ketolides are 14-membered ring macrolidederivatives characterized by a keto group at the C-3 position (Curr.Med. Chem., “Anti-Infective Agents,” 1:15-34 (2002)). Several ketolidecompounds are currently under clinical investigation; however,telithromycin (U.S. Pat. No. 5,635,485) is the first compound in thisfamily to be approved for use.

Liang et al. in U.S. Patent Appl. Pub. No. 2006/0100164, the disclosureof which is incorporated herein by reference, describes a new series ofcompounds, and an illustrative synthesis thereof. These new compoundsshow excellent activity against pathogenic organisms, including thosethat have already exhibited resistance to current therapies. Inparticular, Liang et al. describes compounds including those of formula(I):

and pharmaceutically acceptable salts, solvates, and hydrates thereof;wherein

R¹ is a monosaccharide or polysaccharide;

A is —CH₂—, —C(O)—, —C(O)O—, —C(O)NH—, —S(O)2—, —S(O)2NH—,—C(O)NHS(O)₂—;

B is —(CH₂)_(n)— where n is an integer ranging from 0-10, or B is anunsaturated carbon chain of 2-10 carbons, which may contain any alkenylor alkynyl group;

C represents 1 or 2 substituents independently selected in each instancefrom hydrogen, halogen, hydroxy, alkyl, aralkyl, alkylaryl, alkoxy,heteroalkyl, aryl, heteroaryl, heteroarylalkyl, aminoaryl,alkylaminoaryl, acyl, acyloxy, sulfonyl, ureyl, and carbamoyl, each ofwhich is optionally substituted;

V is —C(O)—, —C(═NR¹¹)—, —CH(NR¹²R¹³)—, or —N(R¹⁴)CH₂—; where R¹¹ ishydroxy or alkoxy, R¹² and R¹³ are each independently selected fromhydrogen, hydroxy, alkyl, aralkyl, alkylaryl, alkoxy, heteroalkyl, aryl,heteroaryl, heteroarylalkyl, dimethylaminoalkyl, acyl, sulfonyl, ureyl,and carbamoyl; and R¹⁴ is hydrogen, hydroxy, alkyl, aralkyl, alkylaryl,alkoxy, heteroalkyl, aryl, heteroaryl, heteroarylalkyl,dimethylaminoalkyl, acyl, sulfonyl, ureyl, or carbamoyl;

W is hydrogen, F, Cl, Br, I, or OH; and

X is hydrogen; and Y is OR⁷; where R⁷ is hydrogen, a monosaccharide ordisaccharide, including aminosugars or halosugars, alkyl, aryl,heteroaryl, acyl, such as 4-nitro-phenylacetyl and 2-pyridylacetyl, or—C(O)NR⁸R⁹, where R⁸ and R⁹ are each independently selected fromhydrogen, hydroxy, alkyl, aralkyl, alkylaryl, heteroalkyl, aryl,heteroaryl, heteroarylalkyl, alkoxy, dimethylaminoalkyl, acyl, sulfonyl,ureyl, and carbamoyl; or X and Y taken together with the attached carbonto form C═O.

In particular, the compound11-N-[[4-(3-aminophenyl)-1,2,3-triazol-1-yl]-butyl]-5-desosaminyl-2-fluoro-3-oxoerythronolideA, 11,12-cyclic carbamate is described by Liang et al.

Due to the importance of these new compounds and others that are beingused to provide beneficial therapies for the treatment of pathogenicorganisms, alternative and/or improved processes for preparing thesecompounds are needed.

For example, the inventors hereof have discovered that side-reactionsoccur, and undesirable side-products and impurities are formed using theconventional synthesis of compounds of formula (I). Those side-reactionsdecrease the overall yield of the desired compounds, and thoseside-products and impurities may complicate the purification of thedesired compounds. Described herein are new processes that may beadvantageous in preparing compounds of formula (I) that avoid suchside-products, and/or may be purified to higher levels of purity.

SUMMARY OF THE INVENTION

In one illustrative embodiment of the invention, processes for preparingcompounds of formula (I) are described:

and pharmaceutically acceptable salts, solvates, and hydrates thereof;wherein

R¹ is a monosaccharide or polysaccharide;

A is —CH₂—, —C(O)—, —C(O)O—, —C(O)NH—, —S(O)2—, —S(O)2NH—,—C(O)NHS(O)₂—;

B is —(CH₂)_(n)— where n is an integer ranging from 0-10, or B is anunsaturated carbon chain of 2-10 carbons, which may contain any alkenylor alkynyl group;

C represents 1 or 2 substituents independently selected in each instancefrom hydrogen, halogen, hydroxy, alkyl, aralkyl, alkylaryl, alkoxy,heteroalkyl, aryl, heteroaryl, heteroarylalkyl, aminoaryl,alkylaminoaryl, acyl, acyloxy, sulfonyl, ureyl, and carbamoyl, each ofwhich is optionally substituted;

V is —C(O)—, —C(═NR¹¹)—, —CH(NR¹²R¹³)—, or —N(R¹⁴)CH₂—; where R¹¹ ishydroxy or alkoxy, R¹² and R¹³ are each independently selected from thegroup consisting of hydrogen, hydroxy, alkyl, aralkyl, alkylaryl,alkoxy, heteroalkyl, aryl, heteroaryl, heteroarylalkyl,dimethylaminoalkyl, acyl, sulfonyl, ureyl, and carbamoyl; R¹⁴ ishydrogen, hydroxy, alkyl, aralkyl, alkylaryl, alkoxy, heteroalkyl, aryl,heteroaryl, heteroarylalkyl, dimethylaminoalkyl, acyl, sulfonyl, ureyl,or carbamoyl;

W is hydrogen, F, Cl, Br, I, or OH;

X is hydrogen; and Y is OR⁷; where R⁷ is hydrogen, a monosaccharide ordisaccharide, including aminosugars or halosugars, alkyl, aryl,heteroaryl, acyl, such as 4-nitro-phenylacetyl and 2-pyridylacetyl, or—C(O)NR⁸R⁹, where R⁸ and R⁹ are each independently selected fromhydrogen, hydroxy, alkyl, aralkyl, alkylaryl, heteroalkyl, aryl,heteroaryl, heteroarylalkyl, alkoxy, dimethylaminoalkyl, acyl, sulfonyl,ureyl, and carbamoyl; or X and Y taken together with the attached carbonto form C═O.

In one aspect of the compounds of formula (I), V is C═O; X and Y aretaken together with the attached carbon to form C═O. In another aspect,R¹ is a monosaccharide that includes an optionally protected 2′-hydroxygroup. In another aspect, R¹ is a monosaccharide that includes aprotected 2′-hydroxy group, where the protecting group is a stericallyhindered acyl group, such as a branched alkyl, aryl, heteroaryl,arylalkyl, arylalkyl, or heteroarylalkyl acyl group, each of which isoptionally substituted. In another aspect, -A-B— is alkylene,cycloalkylene, or arylene; and C is optionally substituted aryl orheteroaryl. In another aspect, R¹ is desosamine; -A-B— is 1,4-butyleneand C is 4-(3-aminophenyl). In another aspect, W is F. In anotheraspect, R¹ is desosamine that includes a protected 2′-hydroxyl group,where the protecting group is a sterically hindered acyl group. Inanother aspect, the sterically hindered acyl group is benzoyl orsubstituted benzoyl.

In another illustrative embodiment, processes for preparing compounds offormula (II) are described:

wherein R^(1a) is a sterically hindered acyl group, and A, B, C, and Vare as described herein. In one aspect of the compounds of formula (II),-A-B— is alkylene, cycloalkylene, or arylene; and C is optionallysubstituted aryl or heteroaryl. In another aspect, R^(1a) is benzoyl;-A-B— is 1,4-butylene and C is 4-(3-aminophenyl).

In another illustrative embodiment, processes for preparing compounds offormula (III) are described:

wherein A, B, C, and V are as described herein. In one aspect of thecompounds of formula (III), -A-B— is alkylene, cycloalkylene, orarylene; and C is optionally substituted aryl or heteroaryl. In anotheraspect, -A-B— is 1,4-butylene and C is 4-(3-aminophenyl).

In another illustrative embodiment, a process is described for preparinga compound of formula (I), (II), or (III) comprising the step of (a)reacting a compound of formula (IV):

wherein R¹ is a monosaccharide that includes a 2′-hydroxyl group, and V,W, X, and Y are as defined herein, with a sterically hindered acylatingagent R^(1a)-L, wherein R^(1a) is a sterically hindered acyl group and Lis a leaving or activating group, to form the corresponding 2′-acylderivative. Illustratively, the process includes the step of (a)reacting compound (1) with a sterically hindered acylating agent to formthe corresponding 2′-acyl or 2′,4″-diacyl derivative, compound (2), asfollows:

wherein W and R^(1a) are as defined herein.

In another illustrative embodiment, a process is described for preparinga compound of formula (I), (II), or (III) comprising the step of (b)reacting a compound of formula (IV) with a carbonylating reagent to forma compound of formula (V):

where L is a leaving group, and R¹, V, W, X, and Y are as definedherein. Illustratively, the process includes the step of (b) reactingcompound (2) with carbonyldiimidazole to prepare compound (3):

wherein R^(1a) and W are as defined herein.

In another illustrative embodiment, a process is described for preparinga compound of formula (I), (II), or (III) comprising the step of (c)reacting a compound of formula (V) with a compound of formula N₃—B-A-NH₂to obtain a compound of formula (VI):

where R¹, A, B, V, W, X, and Y are as described herein. In onevariation, A and B are taken together to form alkylene, cycloalkylene,including spirocycloalkylene, or arylene, each of which is optionallysubstituted. Illustratively, the process includes the step of (c)reacting compound (3) with N₃—B-A-NH₂ to obtain compound (4):

where R^(1a), A, B, and W are as described herein.

In another illustrative embodiment, a process is described for preparinga compound of formula (I), (II), or (III) comprising the step of (d)reacting a compound of formula (I), where X is hydrogen and Y is OR⁷;where R⁷ is a monosaccharide or disaccharide with an acid to prepare thecorresponding compound of formula (I) where R⁷ is hydrogen.Illustratively, the process includes the step of (d) reacting compound(4) with an acid to prepare compound (5):

where R^(1a), A, B, and W are as described herein.

In another illustrative embodiment, a process is described for preparinga compound of formula (I), (II), or (III) comprising the step of (e)oxidizing a compound of formula (I), where X is hydrogen and Y is OH, toprepare the corresponding compound of formula (I), where X and Y aretaken together with the attached carbon to form C═O. Illustratively, theprocess includes the step of (e) oxidizing compound (5) with anoxidizing agent to prepare compound (6):

where R^(1a), A, B, and W are as described herein.

In another illustrative embodiment, a process is described for preparinga compound of formula (I), (II), or (III) comprising the step of (f)reacting a compound of formula (I), where W is hydrogen, with afluorinating agent to prepare the corresponding compound of formula (I)where W is F. Illustratively, the process includes the step of (f)reacting compound (6) with a fluorinating agent to prepare compound (7):

where R^(1a), A, and B are as described herein.

In another illustrative embodiment, a process is described for preparinga compound of formula (I), (II), or (III) comprising the step ofconverting the azide group on a compound of formula (VI) into thecorresponding compound of formula (I) having a 1,2,3-triazole group.Illustratively, a process is described for preparing a compound offormula (I), (II), or (III) comprising the step of (g) reacting acompound of formula (VI) with an R⁴,R⁵-substituted alkyne to obtain acompound of formula (VII):

where R⁴ and R⁵ are each independently selected from the groupconsisting of hydrogen, alkyl, heteroalkyl, aryl, and heteroaryl, eachof which is optionally substituted, and R¹, A, B, V, W, X, and Y are asdescribed herein. In one aspect, both R⁴ and R⁵ are not hydrogen. Inanother aspect, at least one of R⁴ and R⁵ is hydrogen. In one variation,A and B are taken together to form alkylene, cycloalkylene, includingspirocycloalkylene, or arylene, each of which is optionally substituted.Illustratively, the process includes the step of (g) performing aHuisgen cyclization in the presence of a copper catalyst and base oncompound (7) to prepare compound (8):

where R^(1a), A, and B are as described herein.

In another illustrative embodiment, a process is described for preparinga compound of formula (I) comprising the step (h) of reacting a compoundof formula (I), where R¹ is a monosaccharide or polysaccharide having aacyl protecting group, with an alcohol to prepare the correspondingdeprotected compound of formula (I). In one variation, a process isdescribed for preparing a compound of formula (III) comprising the stepof reacting a compound of formula (II) with an alcohol. Illustratively,the process includes the step of (h) reacting compound (8) with analcohol to prepare compound (9):

where A and B are as defined herein.

It is appreciated that the processes described herein may beadvantageously performed simply and cost-effectively. It is furtherappreciated that the processes described herein may be scaled to largeproduction batches. It is further appreciated that the processesdescribed herein are performed in fewer steps than conventionalprocesses. It is further appreciated that the processes described hereinare performed in more convergent steps and fewer linear steps thanconventional processes. It is further appreciated that the processesdescribed herein may concomitantly produce fewer or different sideproducts than known processes. It is further appreciated that theprocesses described herein may yield compounds described herein inhigher purity than known processes.

DETAILED DESCRIPTION

In one illustrative embodiment, processes are described herein forpreparing compounds of formulae (I), (II), and (III) wherein R¹ is amonosaccharide or polysaccharide. In one aspect, the monosaccharide isan aminosugar or a derivative thereof, such as a mycaminose derivatizedat the C-4′ position, desosamine, a 4-deoxy-3-amino-glucose derivatizedat the C-6′ position, chloramphenicol, clindamycin, and the like, or ananalog or derivative of the foregoing. In another aspect, thepolysaccharide is a disaccharide, such as a mycaminose derivatized atthe C-4′ position with another sugar or a 4-deoxy-3-amino-glucosederivatized at the C-6′ position with another sugar, a trisaccharide,such as an aminosugar or halosugar, or an analog or derivative of theforegoing. In another embodiment, R¹ is desosamine, or an analog orderivative thereof. It is to be understood that in this and otherembodiments, derivatives include protected forms of the monosaccharideor polysaccharide.

In another illustrative embodiment, a process is described for preparinga compound of formula (I), (II), or (III) comprising the step of (a) ofreacting a compound of formula (IV):

wherein R¹ is a monosaccharide that includes a 2′-hydroxyl group, and V,W, X, and Y are as defined herein, with a sterically hindered acylatingagent R^(1a)-L, wherein R^(1a) is a sterically hindered acyl group and Lis a leaving or activating group, to form the corresponding 2′-acylderivative. It is appreciated that additional hydroxyl groups present onR¹ or that are included in the group Y may also be acylated in theprocess.

Illustrative sterically hindered acyl or diacyl derivatives include butare not limited to cyclohexylcarbonyl, benzoyl, pivaloyl, and the like.A wide variety of activating groups for forming the acyl derivative maybe used to prepare the required acylating agent, including but notlimited to anhydrides, chlorides, triflates, bromides, and the like. Inone aspect, the sterically hindered acylating agent is benzoicanhydride, or an equivalent activated benzoyl reagent capable of forminga benzoyl ester at the 2′ or both the 2′ and 4′ positions of a compoundof formula (IV), or alternatively compound (1). Illustratively, theprocess includes the step of (a) reacting compound (1) with a stericallyhindered acylating agent to form the corresponding 2′-acyl or2′,4″-diacyl derivative, compound (2), as follows:

wherein W and R^(1a) are as defined herein. In another aspect of thecompounds of formulae (IV), (1), and (2), W is F. In one aspect of theconversion of (1) to (2), R^(1a) is an optionally substituted benzoylgroup, and step (a) includes benzoic anhydride, or an equivalentactivated benzoylating reagent capable of forming the benzoyl ester atthe 2′ or both the 2′ and 4′ positions of a compound of formula (IV), oralternatively compound (1).

Step (a) is generally performed in the presence of a solvent and a base.Illustrative solvents include, but are not limited to, ethyl acetate,dichloromethane, acetone, pyridine and the like, and mixtures thereof.Illustrative bases include but are not limited to inorganic bases, suchas sodium and potassium bicarbonates and carbonates, sodium andpotassium hydroxides, and the like, and mixtures thereof; and aminebases, such as pyridine, dimethylaminopyridine (DMAP), triethylamine(TEA), diisopropylethylamine (DIPEA, Hünigs base),1,4-diazabicyclo[2.2.2]octane (DABCO), and the like, and mixturesthereof. The reaction may be performed at a variety of temperatures,such as in the range from about 0° C. to about 60° C., andillustratively at about 10° C. to about 30° C.

In another illustrative embodiment, a process is described for preparinga compound of formula (I), (II), or (III) comprising the step of (b)reacting a compound of formula (IV) with a carbonylating reagent to forma compound of formula (V):

where L is a leaving group, and R¹, V, W, X, and Y are as definedherein. Step (b) is generally performed in presence of a polar solventand a base to obtain a compound of formula (V). Illustrativecarbonylating agents include methyl chloroformate, benzyl chloroformateand phenylchloroformate, carbonyldiimidazole, phosgene, diphosgene,triphosgene, 1,1′-carbonylbis(2-methylimidazole),[[1,1′-carbonyldipiperidine, bis(pentamethylene)urea]],dimethylcarbonate, diethylcarbonate, dipropylcarbonate, and the like.Illustrative polar solvents include, but are not limited to,dimethylformamide (DMF), acetonitrile, THF, methyl tetrahydrofuran, andthe like, and mixtures thereof. Illustrative bases include, but are notlimited to, DBU, DABCO, TEA, DIPEA, and the like, and mixtures thereof.The reaction may be performed at a variety of temperatures, such as inthe range from about 0° C. to about 60° C., and illustratively atambient temperature. Illustratively, the process includes the step of(b) reacting compound (2) with carbonyldiimidazole to prepare compound(3):

wherein R^(1a) and W are as defined herein. In another illustrativeexample, the process includes the step of reacting compound (2) withcarbonyldiimidazole in the presence of DBU to prepare compound (3). Inanother aspect of the compounds of formulae (V) and (3), W is F. In onevariation, compounds (1V) are first treated with Ms₂O/pyridine, thenDBU/acetone, then NaH/CDI/DMF at −10° C. to prepare compounds (V).

In another illustrative embodiment, a process is described for preparinga compound of formula (I), (II), or (III) comprising the step of (c)reacting a compound of formula (V) with a compound of formula N₃—B-A-NH₂to obtain a compound of formula (VI):

where R¹, A, B, V, W, X, and Y are as described herein. In onevariation, A and B are taken together to form alkylene, cycloalkylene,including spirocycloalkylene, or arylene, each of which is optionallysubstituted. Illustrative groups -A-B— include but are not limited to1,4-butylene, 1,4-pentylene, 1,5-pentylene, 1,1-cyclopropylidene,1,1-cyclopentylidene, 1-cycloprop-1-ylpropyl, and the like. In oneaspect, -A-B— is linear C₂-C₁₀ alkylene. In another aspect, -A-B— islinear C₃-C₅ alkylene. In another aspect, -A-B— is 1,4-butylene.

Step (c) is generally performed in the presence of a polar solvent,including polar protic and polar aprotic solvents, or a mixture thereof.Illustrative polar protic solvents include, but are not limited towater, alcohols, such as methanol, ethanol, isopropanol, n-propanol,n-butanol, iso-butyl alcohol, tert-butyl alcohol, methoxyethanol,ethoxyethanol, pentanol, neo-pentyl alcohol, tert-pentyl alcohol,cyclohexanol, ethylene glycol, propylene glycol, benzyl alcohol,formamide, N-methylacetamide, N-methylformamide, glycerol, and the like,and mixtures thereof. Illustrative polar aprotic solvents include, butare not limited to dimethylformamide (DMF), dimethylacetamide (DMAC),1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU),1,3-dimethyl-2-imidazolidinone (DMI), N-methylpyrrolidinone (NMP),acetonitrile, dimethylsulfoxide, propionitrile, ethyl formate, methylacetate, hexachloroacetone, HMPA, HMPT, acetone, ethyl methyl ketone,ethyl acetate, isopropyl acetate, t-butyl acetate, sulfolane,N,N-dimethylpropionamide, nitromethane, nitrobenzene, tetrahydrofuran(THF), methyl tetrahydrofuran, dioxane, polyethers, and the like, andmixtures thereof. Additionally, step (c) can be performed in thepresence of an additional base. Illustrative bases include, but are notlimited to DBU, DABCO, TEA, DIPEA, and the like, and mixtures thereof.

Illustratively, the process includes the step of (c) reacting compound(3) with N₃—B-A-NH₂ to obtain compound (4)

where R^(1a), A, B, and W are as described herein. In one illustrativeembodiment, the mole equivalent ratio of N₃—B-A-NH₂ to compound (3) isfrom about 4 to 1 to about 3 to 1. In another illustrative embodiment,the mole equivalent ratio of N₃—B-A-NH₂ to compound (3) is about 3 to 1.In another illustrative embodiment, the mole equivalent ratio ofN₃—B-A-NH₂ to compound (3) is about 3 to 1 and the additional base isDBU in a mole equivalent ratio to compound (3) of from about 1 to 1 toabout 0.75 to 1. In another illustrative embodiment, the mole equivalentratio of N₃—B-A-NH₂ to compound (3) is about 3 to 1 and the additionalbase is DBU in a mole equivalent ratio to compound (3) of about 0.75 to1.

In another illustrative embodiment, a process is described for preparinga compound of formula (I), (II), or (III) comprising the step of (d)reacting a compound of formula (I), where X is hydrogen and Y is OR⁷;where R⁷ is a monosaccharide or disaccharide with an acid to prepare thecorresponding compound of formula (I) where R⁷ is hydrogen. Illustrativeacids include, but are not limited to, hydrochloric acid, hydrobromicacid, sulfuric acid, nitric acid, phosphoric acid, perchloric acid,trifluoroacetic acid, formic acid, hydrofluoric acid, and the like, andmixtures thereof. In one variation, the acid is hydrochloric acid. Step(d) is generally performed in a solvent such as water, a polar organicsolvent, including alcohols such as methanol, ethanol, isopropanol,n-propanol, tert-butanol, n-butanol, and the like, and mixtures thereof.Step (d) may be performed at a wide variety of temperatures, includingtemperatures in the range from about 0° C. to about 70° C., andillustratively in the range from about 20° C. to about 60° C.

Illustratively, the process includes the step of (d) reacting compound(4) with an acid to prepare compound (5):

where R^(1a), A, B, and W are as described herein. In one aspect of thecompounds of formulae (VI), (4), and (5), W is F. Illustrative acidsused in step (d) include, but are not limited to trifluoroacetic acid,formic acid, hydrochloric acid, hydrobromic acid, sulfuric acid, nitricacid, phosphoric acid, perchloric acid, hydrofluoric acid, and the like,and mixtures thereof.

In another illustrative embodiment, a process is described for preparinga compound of formula (I), (II), or (III) comprising the step of (e)oxidizing a compound of formula (I), where X is hydrogen and Y is OH, toprepare the corresponding compound of formula (I), where X and Y aretaken together with the attached carbon to form C═O, Step (e) isgenerally performed using conventional oxidizing reagents andconditions, including but not limited to Corey-Kim oxidation, such asdimethylsulfide/N-chlorosuccinimide (DMS/NCS),di-n-butylsulfide/N-chlorosuccinimide, Dess-Martin reagent,Pfitzner-Moffat methods and modifications thereof, Swern conditions,such as DMSO/oxalyl chloride, DMSO/phosphorous pentoxide, DMSO/p-toluenesulfonyl chloride, DMSO/acetic anhydride, DMSO/trifluoroaceticanhydride, and DMSO/thionyl chloride, manganese, chromium and seleniumreagents, tertiary amine oxides, Ni(Ac)₂/hypochlorite,DMSO/EDAC.HCl/pyridine.TFA and the like, and variations thereof, such asby including one or more phase-transfer catalysts.

Illustratively, the process includes the step of (e) oxidizing compound(5) with an oxidizing to prepare compound (6):

where R^(1a), A, B, and W are as described herein. In one aspect of thecompounds of formula (6), W is F. In one illustrative aspect, theoxidizing agent is selected from Swern conditions such asDMSO/EDAC.HCl/pyridine.TFA, Dess-Martin conditions, Corey-Kimconditions, such as dimethylsulfide/N-chlorosuccinimide, Jones reagentand other chromium oxidizing agents, permanganate and other manganeseoxidizing agents, Ni(Ac)₂/hypochlorite, and others. The oxidation isillustratively carried out using dimethylsulfide, N-chlorosuccinimideand triethylamine in methylene chloride at a temperature of from about−20° C. to 0° C. In another illustrative embodiment, the oxidation iscarried out using the Dess-Martin periodinane in methylene chloride at atemperature from about 5° C. to about 30° C. In another illustrativeembodiment, the oxidation is carried out using the Dess-Martinperiodinane in methylene chloride at a temperature from about 5° C. toabout 30° C. utilizing a mole-equivalent ratio of Dess-Martinperiodinane to compound (5) of from about 3.3 to 1 to about 1.3 to 1. Inanother illustrative embodiment, the oxidation is carried out using theDess-Martin periodinane in methylene chloride at a temperature fromabout 5° C. to about 30° C. utilizing a mole-equivalent ratio ofDess-Martin periodinane to compound (5) of about 1.3 to 1.

In another illustrative embodiment, a process is described for preparinga compound of formula (I), (II), or (III) comprising the step of (f)reacting a compound of formula (I), where W is hydrogen, with afluorinating agent to prepare the corresponding compound of formula (I)where W is F. Illustratively, the process includes the step of (f)reacting compound (6) with a fluorinating agent, such as (PhSO₂)₂N—F(NFSI or N-fluorosulfonimide), F-TEDA, F-TEDA-BF₄,1-fluoro-4-hydroxy-1,4-diazoniabicyclo[2.2.2]octanebis(tetrafluoroborate), and the like, in the presence of solvent andbase, such as t-BuOK, to prepare compound (7):

where R^(1a), A, and B are as described herein. It is appreciated thatother combinations of fluorinating agents and bases may be used toprepare compound (7). The fluorination reaction is generally performedin the presence of an inorganic base, such as sodium hydride, sodium orpotassium carbonate, sodium or potassium bicarbonate and the like; anorganic base, such as triethylamine, DABCO, potassium tert-butoxide, andthe like; or a combination thereof. The fluorination reaction isgenerally performed in the presence of a solvent, including but notlimited to, tetrahydrofuran, methyltetrahydrofuran, and the like, ormixtures thereof. In one illustrative embodiment, the fluorination agentis N-fluorosulfonimide, the base is potassium tert-butoxide, and thesolvent is tetrahydrofuran. In another illustrative embodiment the moleequivalent ratio of N-fluorosulfonimide to compound (6) is from about1.3 to 1 to about 1.2 to 1.

In another illustrative embodiment, a process is described for preparinga compound of formula (I), (II), or (III) comprising the step ofconverting the azide group on a compound of formula (VI) into thecorresponding compound of formula (I) having a 1,2,3-triazole group.Illustratively, a process is described for preparing a compound offormula (I), (II), or (III) comprising the step of (g) reacting acompound of formula (VI) with an R⁴,R⁵-substituted alkyne to obtain acompound of formula (VII):

where R⁴ and R⁵ are each independently selected from the groupconsisting of hydrogen, alkyl, heteroalkyl, aryl, and heteroaryl, eachof which is optionally substituted, and R¹, A, B, V, W, X, and Y are asdescribed herein. In one aspect, both R⁴ and R⁵ are not hydrogen. Inanother aspect, at least one of R⁴ and R⁵ is hydrogen. In another aspectof the compounds of formula (VII), W is F. In one variation, A and B aretaken together to form alkylene, cycloalkylene, includingspirocycloalkylene, or arylene, each of which is optionally substituted.Illustrative substituted alkynes include alkynes substituted witharomatic groups, substituted aromatic groups, heterocyclic groups,substituted heterocyclic groups, alkyl groups, branched alkyl groups,substituted alkyl groups, such as alkyl groups substituted with aminogroups, including primary, secondary, and tertiary amino groups, one ormore halogens, hydroxyls, ethers, including alkyl and aromatic ethers,ketones, thioethers, esters, carboxylic acids, cyanos, epoxides, and thelike.

Illustratively, the process includes the step of (g) performing aHuisgen cyclization in the presence of a copper catalyst and base oncompound (7) to prepare compound (8):

where R^(1a), A, and B are as described herein. Huisgen cyclization instep (g) is carried out either solvent-free, in water or in an organicsolvent such as acetonitrile or toluene, in the presence of base.Illustrative bases include but are not limited to organic bases,including alkyl and heteroaryl bases, such as triethylamine,diisopropylethylamine, DABCO, pyridine, lutidine, and the like, andinorganic bases, such as NaOH, KOH, K₂CO₃, NaHCO₃, and the like. Thebase is illustratively diisopropyl ethyl amine (DIPEA). In oneembodiment the ratio of 3-aminophenylethyne to compound (7) is fromabout 1.5 to 1 to about 1.2 to 1 and the ratio of DIPEA to compound (7)is from about 10 to 1 to about 4 to 1. The reaction is carried out attemperatures ranging from 20° C. to 80° C. The reaction may also bepromoted with the use of a catalyst, including but not limited to acopper halide, illustratively copper iodide. The ratio of CuI to azide(VI) or (7) is illustratively from about 0.01 to 1 to about 0.1 to 1. Inone illustrative example, the ratio of CuI to azide (VI) or (7) is 0.03to 1. In an alternate embodiment, the catalyst is an organic catalyst,such as phenolphthalein. Additional reaction conditions are described bySharpless et al. in U.S. Patent Application Publication No. US2005/0222427, Liang et al. in Bioorg. Med. Chem. Lett. 15 (2005)1307-1310, and Romero et al. in Tetrahedron Letters 46 (2005) 1483-1487,the disclosures of which are incorporated herein by reference.

In another illustrative embodiment, a process is described for preparinga compound of formula (I) comprising the step (h) of reacting a compoundof formula (I), where R¹ is a monosaccharide or polysaccharide having aacyl protecting group, with an alcohol to prepare the correspondingdeprotected compound of formula (I). In one variation, a process isdescribed for preparing a compound of formula (III) comprising the stepof reacting a compound of formula (II) with an alcohol. Illustratively,the process includes the step of (h) reacting compound (8) with analcohol to prepare compound (9):

where A and B are as defined herein. The alcohol used in step (h) may beselected from methanol, ethanol, n-propanol, isopropanol, tert-butanol,n-butanol or mixtures thereof. Illustratively, the alcohol is methanol.The reaction is carried out at a temperature of about 0° C. to about100° C. and preferably at about 20° C. to about 70° C. This reaction canalso be carried out in presence of mineral acid selected from groupcomprising of HCl, H₂SO₄ and the like, and mixtures thereof. In oneillustrative embodiment the reaction is carried out in methanol at atemperature of about 55° C.

It is to be understood that the steps described above for the variousprocesses may generally be performed in a different order.

In another embodiment, processes are described herein for preparingcompounds of formulae (I), (II), and (III), where the process includesthe following steps:

where R¹ is a monosaccharide that includes a 2′-hydroxyl group acylatedwith a sterically hindered acylating agent R^(1a)-L, wherein R^(1a) is asterically hindered acyl group and L is a leaving or activating group;and R⁴, R⁵, A, B, V, W, X, and Y are as defined herein. The steps (b),(c), and (g) are performed as described herein.

In another embodiment, processes are described herein for preparingcompounds of formulae (I), (II), and (III), where the process includesthe following steps:

where R¹ is a monosaccharide that includes a 2′-hydroxyl group acylatedwith a sterically hindered acylating agent R^(1a)-L, wherein R^(1a) is asterically hindered acyl group and L is a leaving or activating group;and A, B, and W are as defined herein. The steps (a), (b), (c), (d),(e), (f), (g), and (h) are performed as described herein.

In another embodiment, intermediates useful for the preparation ofcompounds of formulae (I), (II), and (III) are described herein. Suchintermediates include compounds of formula (IV), (V), (VI), and (VII),as well as compounds (1), (2), (3), (4), (5), (6), (7), (8), and (9). Itis understood that such compounds are themselves useful in treatingdiseases, such as bacterial infections, and the like. It is alsounderstood that such compounds may also be useful in the preparation ofantibiotic, antibacterial, anti-infective, and/or antiviralcompositions.

In another embodiment, the processes described herein are useful forpreparing compounds of formulae (I), (II), and (III) in higher yieldsand/or purity than conventional processes. In one aspect, the processesdescribed herein allow for the direct introduction of an azide sidechain onto the macrolide without requiring the prior activation of aside chain hydroxyl group, such as by using tosyl chloride or anequivalent activating group, and subsequent conversion into thecorresponding side chain azide group. The direct introduction of theazide side chain as described herein reduces the overall number ofsynthetic steps that must be performed in preparing compounds offormulae (I), (II), and (III). Conventional syntheses disclose theintroduction of a side chain containing an alcohol group that must beconverted into the azide in a linear sequence in at least two steps.

In another aspect, the processes described herein decrease the number ofside product reactions that take place and correspondingly may decreasethe number of undesired impurities found during the preparation ofcompounds of formulae (I), (II), and (III). The processes describedherein include the use of a sterically hindered acyl group thatfunctions both to protect a hydroxyl group on the saccharide moieties ofthe macrolide and also functions to decrease the likelihood of acylmigration from the saccharide to other functional groups on thecompounds of formulae (I), (II), and (III). For example, it has beendiscovered that unhindered acyl groups, such as acetyl groups, presenton the C-5 saccharide may migrate to other positions on the macrolide.In particular, it has been discovered that in the case of compounds (7),when R^(1a) is acetyl, the acetyl protecting group migrates fromdesosamine to the aniline amino group of side chain, resulting inundesired product and subsequent additional purification steps. Asdescribed herein, the use of a sterically hindered acyl protecting groupsolves the problem of acyl migration reaction during the Huisgencyclization. It is appreciated that avoiding the acyl migration mayresult in both an improved yield as well as improved purity.Accordingly, it has been discovered that compounds of formula (I), andin particular compounds (8) and (9) may be isolated by precipitation,filtration, centrifugation, decantation, and like processes without theneed for chromatographic methods of purification. It is appreciated thatcompounds of formula (I), and in particular compound (9), can be furtherpurified by solid-liquid adsorption chromatography. In one illustrativeembodiment, the adsorbent solid is selected from a reverse-phaseadsorbent, silica gel, alumina, magnesia-silica gel, or the like, andthe elutant is selected from ethyl acetate, isopropyl acetate, methylenechloride, heptane, cyclohexane, toluene, acetonitrile, methanol,isopropanol, ethanol, THF, water or the like, or combinations thereof.In another illustrative example, the solid adsorbent is magnesia-silicagel.

In another aspect, the processes described herein improve the purity ofthe compounds of formulae (I), (II), and (III) described herein, and/orimprove the purification of the compounds described herein. Theprocesses described herein include the use of a sterically hindered acylgroup that functions both to protect a hydroxyl group on the saccharidemoieties of the macrolide and also functions to provide more effectivepurification of the compounds. For example, it has been discovered thatperforming the Huisgen cyclization leads to a mixture of triazolecompound of formula (VII) and unreacted ethyne compound. When thetriazole compound of formula (VII) includes a monosaccharide at R¹ thatis not protected as described herein, the two compounds are difficult toseparate. In contrast, when the triazole compound of formula (VII) doesinclude a 2′-acyl-protected monosaccharide at R¹, the triazole compoundof formula (VII) is unexpectedly more easily separated from theunreacted ethyne compound. Accordingly, it has been discovered thatcompounds of formula (VII), and in particular compounds (8) and (9) maybe isolated by precipitation, filtration, centrifugation, decantation,and like processes without the need for chromatographic methods ofpurification. It is appreciated that compounds of formula (I), and inparticular compounds (9), can be further purified by solid-liquidchromatography. In one illustrative embodiment, the adsorbent solid isselected from a reverse-phase adsorbent, silica gel, alumina,magnesia-silica gel, and the like, and the elutant is selected fromethyl acetate, isopropyl acetate, methylene chloride, heptane,cyclohexane, toluene, acetonitrile, methanol, isopropanol, ethanol, THF,water or the like, or combinations thereof. In another illustrativeexample, the solid adsorbent is magnesia-silica gel.

In another embodiment, compounds of formulae (I), (II), and (III) aredescribed herein as having purities greater than about 98%, greater thanabout 99%, and greater than about 99.5%. In another embodiment,compounds of formulae (I), (II), and (III) are described herein asincluding less than about 1%, less than about 0.5%, less than about0.2%, and less than about 0.1% of any aminophenylethyne compounds. Inanother embodiment, compounds of formulae (I), (II), and (III) aredescribed herein as being substantially free or free of anyaminophenylethyne compounds. In another embodiment, compositionsincluding compounds of formulae (I), (II), and (III) are describedherein as including less than about 1%, less than about 0.5%, less thanabout 0.15%, and less than about 0.1% of any aminophenylethyne compoundscompared to the compounds of formulae (I), (II), and (III) in thecomposition. In another embodiment, compositions including compounds offormulae (I), (II), and (III) are described herein as beingsubstantially free or free of any aminophenylethyne compounds.

The term “aryl,” alone or in combination, refers to an optionallysubstituted aromatic ring system. The term aryl includes monocyclicaromatic rings and polyaromatic rings. Examples of aryl groups includebut are not limited to phenyl, biphenyl, naphthyl and anthryl ringsystems.

The term “heteroaryl” refers to optionally substituted aromatic ringsystems having one or more heteroatoms such as, for example, oxygen,nitrogen, sulfur, selenium and phosphorus. The term heteroaryl mayinclude five- or six-membered heterocyclic rings, polycyclicheteroaromatic ring systems and polyheteroaromatic ring systems.

As used herein the term aralkyl is equivalent to the term arylalkyl anddenotes one or more unsubstituted or substituted monocyclic orunsubstituted or substituted polycyclic aromatic rings attached to analkyl moiety; illustrative examples include but are not limited tobenzyl, diphenylmethyl, trityl, 2-phenylethyl, 1-phenylethyl,2-pyridylmethyl, 4,4′-dimethoxytrityl, and the like.

One skilled in the art will also readily recognize that where membersare grouped together in a common manner, such as in a Markush group, thepresent invention encompasses not only the entire group listed as awhole, but each member of the group individually and all possiblesubgroups of the main group. Accordingly, for all purposes, the presentinvention encompasses not only the main group, but also the main groupabsent one or more of the group members. The present invention alsoenvisages the explicit exclusion of one or more of any of the groupmembers in the claimed invention.

The term saccharide includes monosaccharides, disaccharides, andpolysaccharides, each of which is optionally substituted. The term alsoincludes sugars and deoxysugars optionally substituted with amino,amido, ureyl, halogen, nitrile, or azido groups. Illustrative examplesinclude, glucosamine, N-acetylglucosamine, desosamine, forosamine,sialic acid, and the like.

The processes described herein are further illustrated by the followingexamples. The following examples are intended to be illustrative andshould not be construed or considered to be limiting in any manner.

EXAMPLES Example 1

Preparation of 2′,4″-di-O-benzoyl-6-O-methylerythromycin A. 125 mL ofethyl acetate was added to 25 g clarithromycin A. 26.5 g benzoicanhydride, 5.7 g 4-dimethylamino pyridine and 6.7 g triethylamine wereadded to the reaction mixture at 25° C. to 35° C. The reaction mixturewas stirred for about 70 hours at ambient temperature. After completionof the reaction, ethyl acetate was distilled out to obtain the titlecompound.

Example 2

Preparation of10,11-anhydro-2′,4″-di-O-benzoyl-12-O-imidazolylcarbonyl-6-O-methylerythromycinA. Dimethylformamide (DMF, 100 mL) was added to2′,4″-di-O-benzoyl-6-O-methylerythromycin A at 25-35° C., then1,8-diazabicyclo[5.4.0]undec-7-ene (DBU 6.4 g) was added to the reactionmixture and stirred at ambient temperature. 1,1′-Carbonyldiimidazole(CDI, 17 g) was added to the reaction and it was stirred untilcompletion at ambient temperature. The title compound is isolated byaddition of water, and collecting the resulting precipitate.

Example 3

Preparation of2′,4″-di-O-benzoyl-11-N-(4-Azidobutyl)-6-O-methylerythromycin A11,12-cyclic carbamate. DMF (50 mL) was added to10,11-anhydro-2′,4″-di-O-benzoyl-12-O-imidazolylcarbonyl-6-O-methylerythromycinA (10 g) at 25° C. to 35° C. 4-Azido butyl amine (4.4 g) and DBU (1.5 g)were added to the reaction mixture, which was stirred at 25° C. to 35°C. until the reaction was complete. The mixture was then treated withcold water, and the resulting solid precipitate was collected. The solidwas treated with dichloromethane followed by extraction and removal ofsolvent to give the title compound. The mole-equivalent ratio of 4-azidobutyl amine to10,11-anhydro-2′,4″-di-O-benzoyl-12-O-imidazolylcarbonyl-6-O-methylerythromycinA is optionally selected to be from about 4 to 1 to about 3 to 1. Themolar ratio of DBU to10,11-anhydro-2′,4″-di-O-benzoyl-12-O-imidazolylcarbonyl-6-O-methylerythromycinA is optionally selected to be from about 1 to 1 to about 0.75 to 1.

Example 4

Preparation of11-N-(4-Azidobutyl)-5-(2′-benzoyldesosaminyl)-3-hydroxy-6-O-methylerythronolideA 11,12-cyclic carbamate. Acetone (10 mL) was added to2′,4″-di-O-benzoyl-11-N-(4-Azidobutyl)-6-O-methylerythromycin A11,12-cyclic carbamate (5 g) to obtain a clear solution at 25° C. to 35°C. Dilute HCl (10 mL) was added to the reaction mixture and it wasstirred for 24 hours at ambient temperature. After the completion of thereaction, the reaction mixture was extracted with ethyl acetate andtreated with a sodium hydroxide solution to give the title compound.

Example 5

Preparation of11-N-(4-Azidobutyl)-5-(2′-benzoyldesosaminyl)-3-oxo-6-O-methylerythronolideA 11,12-cyclic carbamate. Dichloromethane (50 mL)was added toN-chlorosuccinimide (2 g) under nitrogen at room temperature cooled to0° C. Dimethylsulfide (1.8 mL) was added slowly to the reaction mixtureat 0° C. under stirring.11-N-(4-Azidobutyl)-5-(2′-benzoyldesosaminyl)-3-hydroxy-6-O-methylerythronolideA 11,12-cyclic carbamate 11,12-cyclic carbamate (5 g) dissolved indichloromethane (20 mL) was added drop wise to the reaction mixture at0° C. under stirring. The mixture was cooled to about −20° C. and asolution of triethylamine (4 mL) in dichloromethane (5 mL) was added tothe reaction mixture and stirred for 30 minutes. After completion of thereaction, it is treated with saturated sodium bicarbonate solution andthe organic layer was isolated. The title compound was obtained bydistillation of the solvent. Additional reaction conditions aredescribed by Plata, et al, Tetrahedron 60 (2004), 10171-10180, theentire disclosure of which is incorporated herein by reference.

Example 5A

Preparation of11-N-(4-Azidobutyl)-5-(2′-benzoyldesosaminyl)-3-oxo-6-O-methylerythronolideA 11,12-cyclic carbamate. Oxidation of11-N-(4-azidobutyl)-5-(2′-benzoyldesosaminyl)-3-hydroxy-6-O-methylerythronolideA 11,12-cyclic carbamate (100 g, 0.1225 moles) with Dess-Martinperiodinane (170 g, 0.400 moles) was carried out in dichloromethane at10-15° C. Reaction mixture was stirred at 20-25° C. for 2 hr. Thereaction mixture was quenched with 5% aqueous sodium hydroxide solution.The organic layer was washed with water and sat. solution of sodiumchloride. The solvent was removed by distillation of the organic layerand the product was isolated from a mixture of diisopropyl ether andhexane. The separated solid was filtered and dried under vacuum at30-35° C. to give the title compound. The mole-equivalent ratio ofDess-Martin periodinane to11-N-(4-azidobutyl)-5-(2′-benzoyldesosaminyl)-3-hydroxy-6-O-methylerythronolideA 11,12-cyclic carbamate is optionally from about 3.3 to 1 to about 1.3to 1.

Example 6

Preparation of11-N-(4-Azidobutyl)-5-(2′-benzoyldesosaminyl)-3-oxo-2-fluoro-6-O-methylerythronolideA, 11,12-cyclic carbamate. To a solution of11-N-(4-azidobutyl)-5-(2′-benzoyldesosaminyl)-3-oxo-6-O-methylerythronolideA 11,12-cyclic carbamate (5 g) in tetrahydrofuran (400 mL) was added 7.3mL of potassium tert-butoxide followed by addition of 2 g ofN-fluorobenzenesulfonimide. After about 1 hour, the mixture was quenchedwith water followed by extraction with dichloromethane. The organiclayers were separated and concentrated to obtain the title compound.

Example 6B Example 6

Preparation of11-N-(4-Azidobutyl)-5-(2′-benzoyldesosaminyl)-3-oxo-2-fluoro-6-O-methylerythronolideA, 11,12-cyclic carbamate. To a solution of11-N-(4-azidobutyl)-5-(2′-benzoyldesosaminyl)-3-oxo-6-O-methylerythronolideA 11,12-cyclic carbamate (100 g) in tetrahydrofuran (2200 mL) was addedpotassium tert-butoxide (28 g) at −20° C. to −5° C. followed by theaddition of N-fluorobenzenesulfonimide (54 g). After about 1 hour, Themixture was quenched with 5% aqueous sodium bicarbonate solution. Theseparated organic layer was washed with water and saturated sodiumchloride solution. The solvent was removed by distillation and remainingmaterial was crystallized from the mixture of isopropyl alcohol andwater, filtered, and dried under vacuum at 40-45° C. to yield the titlecompound. The mole-equivalent ratio of N-fluorobenzenesulfonimide to11-N-(4-azidobutyl)-5-(2′-benzoyldesosaminyl)-3-oxo-6-O-methylerythronolideA 11,12-cyclic carbamate is optionally from about 1.6 to 1 to about 1.2to 1. The ratio of solvent (mL) to11-N-(4-azidobutyl)-5-(2′-benzoyldesosaminyl)-3-oxo-6-O-methylerythronolideA 11,12-cyclic carbamate is optionally from about 22 to 1 to about 17 to1.

Example 7

11-N-(3-amino-phenyl-1-ylmethyl-[1,2,3]-triazole-1-yl]butyl)-5-(2′-benzoyldesosaminyl)-3-oxo-2-fluoro-erythronolideA, 11,12-cyclic carbamate.11-N-(3-amino-phenyl-1-ylmethyl-[1,2,3]-triazole-1-yl]butyl)-5-(2′-benzoyldesosaminyl)-3-oxo-2-fluoro-6-O-methylerythronolideA, 11,12-cyclic carbamate (10 g), 3-ethynylphenylamine (2.11 g), copperiodide (0.3 g) and diisopropylethylamine (15.5 g) were taken inacetonitrile (200 mL) and stirred for 20 hours at room temperature.After completion of the reaction, the reaction mixture was quenched withdilute HCl and extracted with dichloromethane. The organic layer wasneutralized with a bicarbonate solution, dried and concentrated toobtain the title compound.

Example 7B

11-N-(3-amino-phenyl-1-ylmethyl-[1,2,3]-triazole-1-yl]butyl)-5-desosaminyl-3-oxo-2-fluoro-erythronolideA, 11,12-cyclic carbamate.11-N-(3-amino-phenyl-1-ylmethyl-[1,2,3]-triazole-1-yl]butyl)-5-(2′-benzoyldesosaminyl)-3-oxo-2-fluoro-6-O-methylerythronolideA, 11,12-cyclic carbamate (100 g), 3-ethynylphenylamine (20 g), copperiodide (10 g) and diisopropylethylamine (155 g) were taken inacetonitrile 600 mL) and stirred for 12 hours at 25° C. to 30° C. Themole equivalent ratio of 3-ethynylphenylamine to11-N-(3-amino-phenyl-1-ylmethyl-[1,2,3]-triazole-1-yl]butyl)-5-(2′-benzoyldesosaminyl)-3-oxo-2-fluoro-6-O-methylerythronolideA, 11,12-cyclic carbamate is optionally from about 1.5 to 1 to about 1.2to 1. After completion of the reaction, the reaction mixture was pouredinto dilute HCl and extracted with diisopropylether. The aqueous layerwas extracted with dichloromethane. The dichloromethane layer wasneutralized with aqueous sodium bicarbonate, dried (NaSO₄) andconcentrated to obtain the title compound. This material was added tomethanol (600 mL) and the resulting mixture heated at 50° C. to 55° C.for 12 hours. The solution was treated with activated carbon (10 g),filtered and concentrated under reduced pressure. The residue wasdissolved in a mixture of water and EtOAc. The pH of the aqueous phasewas adjusted to about 3.5. The organic layer was separated and theaqueous layer was extracted with ethyl acetate (two times) followed bydiisopropylether (two times). The resulting aqueous layer was added toaqueous ammonia (1000 mL of about 4% ammonia). The precipitated solidwas collected by filtration, washed with water, until the pH of the washwas about 7 to 8 and dried under reduced pressure to obtain the titlecompound. This material is optionally further purified byrecrystallization from ethanol.

Example 8

11-N-(3-amino-phenyl-1-ylmethyl-[1,2,3]-triazole-1-yl]butyl)-5-desosaminyl-3-oxo-2-fluoro-erythronolideA, 11,12-cyclic carbamate.11-N-(3-amino-phenyl-1-ylmethyl-[1,2,3]-triazole-1-yl]butyl)-5-(2′-benzoyldesosaminyl)-3-oxo-2-fluoro-erythronolideA, 11,12-cyclic carbamate (6 g) was dissolved in methanol (60 mL) andheated at reflux for 7 hours. After the completion of reaction, themixture was concentrated, diluted with diisopropylether (30 mL) andstirred at ambient temperature for 2 hours. The resulting solid wascollected by filtration. The solid is optionally purified byprecipitation, crystallization or chromatography. Optionally, thematerial is converted to a salt by addition of an acid followed byprecipitation of the salt. Analysis of the material indicated the titlecompound with >98% purity. Examples 1-8 were repeated to prepare a 5 kgsample of the title compound of Example 8. It was determined that thelarge sample contained less than about 0.1% aminophenylethynes, or about0.07% aminophenylethynes.

Example 9

Purification of11-N-(3-amino-phenyl-1-ylmethyl-[1,2,3]-triazole-1-yl]butyl)-5-desosaminyl-3-oxo-2-fluoro-erythronolideA, 11,12-cyclic carbamate. Florisil (21 kg) was loaded into a columncontaining 63 L of ethyl acetate. A solution of 1.4 kg of11-N-(3-amino-phenyl-1-ylmethyl-[1,2,3]-triazole-1-yl]butyl)-5-desosaminyl-3-oxo-2-fluoro-erythronolideA, 11,12-cyclic carbamate in 14 L ethyl acetate and 0.7 L ofacetonitrile is passed through the column. The eluent is collected.Ethyl acetate (112 L) is passed through the column and the eluent iscombined with the first fraction. This process is repeated 4 additionaltimes. The combined eluent solutions are concentrated and the residuewas dissolved in 39 L of ethyl alcohol by heating to 50-55° C. Thevolume is reduce to about 22 L and cooled to 25-30° C. The solution isstirred for 5-6 hours. The resultant solid is collected and washed withcold ethyl alcohol. The wet cake is dissolved in a solution of ethylacetate/acetonitrile (15 L/0.5 L per kg of wet cake) by heating to40-45° C. Additional ethyl acetate (20 L per kg of wet cake) is added tothe solution. This solution is passed through a Florisil column (15kg/kg wet cake). The eluent is collected. The column is flushed withethyl acetate (80 L per kg of wet cake). The eluent is collected andcombine with the first eluent. The combined eluent solutions areconcentrated and the residue was dissolved in 39 L of ethyl alcohol byheating to 50-55° C. The volume is reduce to about 22 L and cooled to25-30° C. The solution is stirred for 5-6 hours. The resultant solid iscollected and washed with cold ethyl alcohol. The filter cake is addedto 50 L of water cooled to 10-15° C. Conc. HCl (0.97 L) is slowly addedat 10-15° C. to obtain a clear solution. The solution is filtered. Thefiltrate is slowly added to a solution of aqueous ammonia (0.79 Lammonia in 28 L water) at 10-25° C. The resulting mixture is stirred for30 minutes and the solid is collected by centrifugation. The solid wasdried at 45-50° C. until the moisture content was not more than 1.5%.

Example 9A

11-N-(3-amino-phenyl-1-ylmethyl-[1,2,3]-triazole-1-yl]butyl)-5-desosaminyl-3-oxo-2-fluoro-erythronolideA, 11,12-cyclic carbamate is optionally purified by dissolving materialin a minimum amount of a solvent and adding an acid to the mixture toform a solid that precipitates from the solvent or precipitates afteraddition of a second solvent to the acidified mixture.

Example 10

Preparation of the 4-azido-butylamine. 1,4-Dibromobutane was dissolvedin warm DMF and treated with sodium azide (three mole-equivalents).After the reaction was complete, the reaction mixture was diluted withwater and the 1,4-diazido-butane was extracted into methyl t-butylether. Triphenylphosphine (1.08 mole-equivalents) was added the solutionof 1,4-diazido-butane. When the reaction was complete the mixture wasdiluted with 5% hydrochloric acid until hydrolysis was complete. Theacidic aqueous layer was separated, made basic with dilute sodiumhydroxide. The resulting product was extracted into methylene chloride.The organic layer was separated and concentrated under reduced pressureto obtain the title material. The preparation of 1,4-diazido-butane isoptionally performed with a mole-equivalent ratio to sodium azide offrom about 1 to 3 to about 1 to 5. 1,4-Diazido-butane is optionallyreduced to 4-azido-butylamine with other reducing agents, for example,sodium borohydride.

Comparative Example 1

The process described by Romero et al, in Tetrahedron letters,46:1483-1487 (2005), for the preparation of macrolides is as follows:

(a) 4-aminobutan-1-ol, DMF; (b) TsCl, pyridine; (c) NaN₃, DMF, 80° C. Inthis Example, the azide side chain is introduced by first reacting theactivated acylated allylic alcohol at C-12 with 4-amino-1-butanol,subsequently activating the side chain hydroxyl group with tosylchloride, and finally reacting with NaN₃ to prepare the correspondingside chain azide (see generally, US Patent Appl. Pub. No. 2006/0100164).This comparative process necessarily requires at least two steps tointroduce the azide group onto the side chain.

Comparative Example 2

The process described by Liang et al. and Romero et al. (Tetrahedronletters, 46:1483-1487 (2005)) for the preparation of macrolides is asfollows:

where the Huisgen reaction is performed on the unprotected desosamine.It was discovered that this lack of protection lead to the formation ofside products. It was also surprisingly discovered that the reagent3-aminophenylethyne was difficult to remove from the unprotected finalproduct triazole. Further, it was discovered that conversion of thecorresponding 2′-acetyl protected derivative to the 1,2,3-triazol in aHuisgen cyclization lead to concomitant acetyl migration from thedesosamine sugar to the amino group of side chain aniline fragment,resulting in undesired product formation, correspondingly lower yields,and the need for subsequent purification steps.

1-28. (canceled)
 29. A process for preparing a compound of formula (I)comprising the step (h) of reacting a compound of formula (I), where R¹is a monosaccharide or polysaccharide that includes a 2′-hydroxyl groupacylated with R^(1a) wherein R^(1a) is a sterically hindered acyl group,with an alcohol to prepare the corresponding deprotected compound offormula (I)

wherein R¹ is a monosaccharide or polysaccharide that includes a2′-hydroxy group; A is —CH₂—, —C(O)—, —C(O)O—, —C(O)NH—, —S(O)2—,—S(O)2NH—, —C(O)NHS(O)₂—; B is —(CH₂)_(n)— where n is an integer rangingfrom 0-10, or B is an unsaturated carbon chain of 2-10 carbons; Crepresents 1 or 2 substituents independently selected in each instancefrom the group consisting of hydrogen, halogen, hydroxy, alkyl, aralkyl,alkylaryl, alkoxy, heteroalkyl, aryl, heteroaryl, heteroarylalkyl,aminoaryl, alkylaminoaryl, acyl, acyloxy, sulfonyl, ureyl, andcarbamoyl, each of which is optionally substituted; V is —C(O)—,—C(═NR¹¹)—, —CH(NR¹²R¹³)—, or —N(R¹⁴)CH₂—; where R¹¹ is hydroxy oralkoxy, R¹² and R¹³ are each independently selected from the groupconsisting of hydrogen, hydroxy, alkyl, aralkyl, alkylaryl, alkoxy,heteroalkyl, aryl, heteroaryl, heteroarylalkyl, dimethylaminoalkyl,acyl, sulfonyl, ureyl, and carbamoyl; R¹⁴ is hydrogen, hydroxy, alkyl,aralkyl, alkylaryl, alkoxy, heteroalkyl, aryl, heteroaryl,heteroarylalkyl, dimethylaminoalkyl, acyl, sulfonyl, ureyl, orcarbamoyl; W is hydrogen, F, Cl, Br, I, or OH; X is hydrogen; and Y isOR⁷; where R⁷ is hydrogen, a monosaccharide, a disaccharide, alkyl,aryl, heteroaryl, acyl, or —C(O)NR⁸R⁹, where R⁸ and R⁹ are eachindependently selected from hydrogen, hydroxy, alkyl, aralkyl,alkylaryl, heteroalkyl, aryl, heteroaryl, heteroarylalkyl, alkoxy,dimethylaminoalkyl, acyl, sulfonyl, ureyl, or carbamoyl; or X and Ytaken together with the attached carbon to form C═O; andpharmaceutically acceptable salts, solvates, and hydrates thereof. 30.The process of claim 29 wherein the sterically hindered acyl groupR^(1a) is benzoyl or substituted benzoyl.
 31. A process for preparing acompound of formula (I)

wherein R¹ is a monosaccharide or polysaccharide; A is —CH₂—, —C(O)—,—C(O)O—, —C(O)NH—, —S(O)2—, —S(O)2NH—, —C(O)NHS(O)2-; B is —(CH₂)_(n)—where n is an integer ranging from 0-10, or B is an unsaturated carbonchain of 2-10 carbons; C represents 1 or 2 substituents independentlyselected in each instance from the group consisting of hydrogen,halogen, hydroxy, alkyl, aralkyl, alkylaryl, alkoxy, heteroalkyl, aryl,heteroaryl, heteroarylalkyl, aminoaryl, alkylaminoaryl, acyl, acyloxy,sulfonyl, ureyl, and carbamoyl, each of which is optionally substituted;V is —C(O)—, —C(═NR¹¹)—, —CH(NR¹²R¹³)—, or —N(R¹⁴)CH₂—; where R′¹ ishydroxy or alkoxy, R¹² and R¹³ are each independently selected from thegroup consisting of hydrogen, hydroxy, alkyl, aralkyl, alkylaryl,alkoxy, heteroalkyl, aryl, heteroaryl, heteroarylalkyl,dimethylaminoalkyl, acyl, sulfonyl, ureyl, and carbamoyl; R¹⁴ ishydrogen, hydroxy, alkyl, aralkyl, alkylaryl, alkoxy, heteroalkyl, aryl,heteroaryl, heteroarylalkyl, dimethylaminoalkyl, acyl, sulfonyl, ureyl,or carbamoyl; W is hydrogen, F, Cl, Br, I, or OH; X is hydrogen; and Yis OR⁷; where R⁷ is hydrogen, a monosaccharide, a disaccharide, alkyl,aryl, heteroaryl, acyl, or —C(O)NR⁸R⁹, where R⁸ and R⁹ are eachindependently selected from hydrogen, hydroxy, alkyl, aralkyl,alkylaryl, heteroalkyl, aryl, heteroaryl, heteroarylalkyl, alkoxy,dimethylaminoalkyl, acyl, sulfonyl, ureyl, or carbamoyl; or X and Ytaken together with the attached carbon to form C═O; andpharmaceutically acceptable salts, solvates, and hydrates thereof; theprocess comprising the step of (c) reacting a compound of formula (V)

with a compound of formula N₃—B-A-NH₂ to obtain a compound of formula(VI)

wherein R^(1b) is a saccharide that includes a 2′-hydroxyl groupacylated with R^(1a) wherein R^(1a) is a sterically hindered acyl group.32. A process for preparing a compound of formula (I)

(I) wherein R¹ is a monosaccharide or polysaccharide; A is —CH₂—,—C(O)—, —C(O)O—, —C(O)NH—, —S(O)2—, —S(O)2NH—, —C(O)NHS(O)₂—; B is—(CH₂)_(n)— where n is an integer ranging from 0-10, or B is anunsaturated carbon chain of 2-10 carbons; C represents 1 or 2substituents independently selected in each instance from the groupconsisting of hydrogen, halogen, hydroxy, alkyl, aralkyl, alkylaryl,alkoxy, heteroalkyl, aryl, heteroaryl, heteroarylalkyl, aminoaryl,alkylaminoaryl, acyl, acyloxy, sulfonyl, ureyl, and carbamoyl, each ofwhich is optionally substituted; V is —C(O)—, —C(═NR¹¹)—, —CH(NR¹²R¹³)—,or —N(R¹⁴)CH₂—; where R¹¹ is hydroxy or alkoxy, R¹² and R¹³ are eachindependently selected from the group consisting of hydrogen, hydroxy,alkyl, aralkyl, alkylaryl, alkoxy, heteroalkyl, aryl, heteroaryl,heteroarylalkyl, dimethylaminoalkyl, acyl, sulfonyl, ureyl, andcarbamoyl; R¹⁴ is hydrogen, hydroxy, alkyl, aralkyl, alkylaryl, alkoxy,heteroalkyl, aryl, heteroaryl, heteroarylalkyl, dimethylaminoalkyl,acyl, sulfonyl, ureyl, or carbamoyl; W is hydrogen, F, Cl, Br, I, or OH;X is hydrogen; and Y is OR⁷; where R⁷ is hydrogen, a monosaccharide, adisaccharide, alkyl, aryl, heteroaryl, acyl, or —C(O)NR⁸R⁹, where R⁸ andR⁹ are each independently selected from hydrogen, hydroxy, alkyl,aralkyl, alkylaryl, heteroalkyl, aryl, heteroaryl, heteroarylalkyl,alkoxy, dimethylaminoalkyl, acyl, sulfonyl, ureyl, or carbamoyl; or Xand Y taken together with the attached carbon to form C═O; andpharmaceutically acceptable salts, solvates, and hydrates thereof; theprocess comprising the step of (g) reacting a compound of formula (VI)as defined in claim 31 with an R⁴,R⁵-substituted alkyne to obtain acompound of formula (VII)

wherein R⁴ and R⁵ are each independently selected from the groupconsisting of hydrogen, alkyl, heteroalkyl, aryl, and heteroaryl, eachof which is optionally substituted; and R^(1b) is a saccharide thatincludes a 2′-hydroxyl group acylated with R^(1a) wherein R^(1a) is asterically hindered acyl group.
 33. The process of any one of claims 29to 32 wherein V is C═O; and X and Y are taken together with the attachedcarbon to form C═O.
 34. The process of any one of claims 29 to 32wherein R¹ is a monosaccharide that includes an optionally protected2′-hydroxy group.
 35. The process of any one of claims 29, 31 and 32wherein R^(1a) is selected from the group consisting of branched alkyl,aryl, heteroaryl, arylalkyl, and heteroarylalkyl acyl groups, each ofwhich is optionally substituted.
 36. The process of any one of claims 29to 32 wherein -A-B— is alkylene, and C is optionally substituted aryl orheteroaryl.
 37. The process of any one of claims 29 to 32 wherein R¹ isdesosamine; -A-B— is 1,4-butylene and C is 4-(3-aminophenyl).
 38. Theprocess of any one of claims 29 to 32 wherein W is F.
 39. A compound ofthe formula

wherein R¹ is a saccharide that includes a 2′-hydroxyl group acylatedwith R^(1a), wherein R^(1a) is a sterically hindered acyl group; A is—CH₂—, —C(O)—, —C(O)O—, —C(O)NH—, —S(O)2—, —S(O)2NH—, —C(O)NHS(O)2-; Bis —(CH₂)_(n)— where n is an integer ranging from 0-10, or B is anunsaturated carbon chain of 2-10 carbons, which may contain any alkenylor alkynyl group; V is —C(O)—, —C(═NR¹¹)—, —CH(NR¹²R¹³)—, or—N(R¹⁴)CH₂—; where R¹¹ is hydroxy or alkoxy, R¹² and R¹³ are eachindependently selected from the group consisting of hydrogen, hydroxy,alkyl, aralkyl, alkylaryl, alkoxy, heteroalkyl, aryl, heteroaryl,heteroarylalkyl, dimethylaminoalkyl, acyl, sulfonyl, ureyl, andcarbamoyl; R¹⁴ is hydrogen, hydroxy, alkyl, aralkyl, alkylaryl, alkoxy,heteroalkyl, aryl, heteroaryl, heteroarylalkyl, dimethylaminoalkyl,acyl, sulfonyl, ureyl, or carbamoyl; W is hydrogen, F, Cl, Br, I, or OH;and X is hydrogen; and Y is OR⁷; where R⁷ is hydrogen, a monosaccharide,a disaccharide, alkyl, aryl, heteroaryl, acyl, or —C(O)NR⁸R⁹, where R⁸and R⁹ are each independently selected from hydrogen, hydroxy, alkyl,aralkyl, alkylaryl, heteroalkyl, aryl, heteroaryl, heteroarylalkyl,alkoxy, dimethylaminoalkyl, acyl, sulfonyl, ureyl, or carbamoyl.
 40. Acompound of the formula

wherein A is —CH₂—, —C(O)—, —C(O)O—, —C(O)NH—, —S(O)2—, —S(O)2NH—,—C(O)NHS(O)2-; B is —(CH₂)_(n)— where n is an integer ranging from 0-10,or B is an unsaturated carbon chain of 2-10 carbons; W is hydrogen, F,Cl, Br, I, or OH; and R^(1a) is a sterically hindered acyl group. 41.(canceled)
 42. A compound of the formula

in greater than about 98% purity; wherein A is —CH₂—, —C(O)—, —C(O)O—,—C(O)NH—, —S(O)2—, —S(O)2NH—, —C(O)NHS(O)2—; B is —(CH₂)_(n)— where n isan integer ranging from 0-10, or B is an unsaturated carbon chain of2-10 carbons.
 43. A composition comprising a compound of the formula

wherein A is —CH₂—, —C(O)—, —C(O)O—, —C(O)NH—, —S(O)2—, —S(O)2NH—,—C(O)NHS(O)2-; B is —(CH₂)_(n)— where n is an integer ranging from 0-10,or B is an unsaturated carbon chain of 2-10 carbons; and where thecomposition includes less than about 0.15% of an aminophenylethynecompared to the compound.
 44. A compound of the formula

wherein R¹ is a saccharide that includes a 2′-hydroxyl group acylatedwith R^(1a), wherein R^(1a) is a sterically hindered acyl group; A is—CH₂—, —C(O)—, —C(O)O—, —C(O)NH—, —S(O)2—, —S(O)2NH—, —C(O)NHS(O)2-; Bis —(CH₂)_(n)— where n is an integer ranging from 0-10, or B is anunsaturated carbon chain of 2-10 carbons; V is —C(O)—, —C(═NR¹¹)—,—CH(NR¹²R¹³)—, or —N(R¹⁴)CH₂—; where R¹¹ is hydroxy or alkoxy, R¹² andR¹³ are each independently selected from the group consisting ofhydrogen, hydroxy, alkyl, aralkyl, alkylaryl, alkoxy, heteroalkyl, aryl,heteroaryl, heteroarylalkyl, dimethylaminoalkyl, acyl, sulfonyl, ureyl,and carbamoyl; R¹⁴ is hydrogen, hydroxy, alkyl, aralkyl, alkylaryl,alkoxy, heteroalkyl, aryl, heteroaryl, heteroarylalkyl,dimethylaminoalkyl, acyl, sulfonyl, ureyl, or carbamoyl; W is hydrogen,F, Cl, Br, I, or OH; X is hydrogen; and Y is OR⁷; where R⁷ is hydrogen,a monosaccharide, a disaccharide, alkyl, aryl, heteroaryl, acyl, or—C(O)NR⁸R⁹, where R⁸ and R⁹ are each independently selected fromhydrogen, hydroxy, alkyl, aralkyl, alkylaryl, heteroalkyl, aryl,heteroaryl, heteroarylalkyl, alkoxy, dimethylaminoalkyl, acyl, sulfonyl,ureyl, or carbamoyl; or X and Y taken together with the attached carbonto form C═O; and R⁴ and R⁵ are each independently selected from thegroup consisting of hydrogen, alkyl, heteroalkyl, aryl, and heteroaryl,each of which is optionally substituted.
 45. The compound of claim 39,40 or 44 wherein R^(1a) is benzoyl.